Is NOTCH2 p.Pro2329Ser (c.6985C>T) pathogenic?

NOTCH2 p.Pro2329Ser (c.6985C>T) is classified Uncertain significance in NOTCH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0679); Ultra-rare (popmax 0.0251%, amr); Associated with acroosteolysis dominant type.

What condition is associated with NOTCH2 p.Pro2329Ser (c.6985C>T)?

NOTCH2 p.Pro2329Ser (c.6985C>T) is associated with acroosteolysis dominant type (ClinVar).

How common is NOTCH2 p.Pro2329Ser (c.6985C>T) in the general population?

NOTCH2 p.Pro2329Ser (c.6985C>T) is ultra-rare (popmax 0.0251%, amr) (gnomAD).

What do computational predictors say about NOTCH2 p.Pro2329Ser (c.6985C>T)?

AlphaMissense predicts likely benign (score 0.0679) — an in-silico prediction, not a clinical call.

NOTCH2 p.Pro2329Ser

c.6985C>T · rs1278379367 · VCV593210

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0679 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0251%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

acroosteolysis dominant type

Computational evidence

Protein change
AlphaMissense	0.0679	likely benign
REVEL	0.169	moderately benign-leaning
SaProt	LLR -6.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,256 bp · p 0.14 · regional, not allelic
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0251% Admixed American · 15/59,826 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0125%

Overall 0.000995% 16/1,608,000 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0251%	3,988
Remaining individualsnot grpmax-eligible	0.00161%	62,192

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NOTCH2
Protein: p.Pro2329Ser
Coding: c.6985C>T
MANE Select: NM_024408
dbSNP: rs1278379367
Type: single nucleotide variant
Location: chr1:119915737 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 2329: a UniProt-annotated variant site (in hjcys); a UniProt-annotated variant site (in hjcys; loss of interaction with fbw7; decreased ubiquitination)

Full NOTCH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

acroosteolysis dominant type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NOTCH2 p.Arg2003Ter Pathogenic/Likely pathogenic ★★ same condition
NOTCH2 p.Arg2400Ter Pathogenic ★★ same condition
NOTCH2 p.Gln2223Ter Pathogenic ★★ same condition
NOTCH2 p.Gln2263Ter Pathogenic ★★ same condition
NOTCH2 p.Gln2285Ter Pathogenic/Likely pathogenic ★★ same condition
NOTCH2 c.2753-8T>A Uncertain significance ★★ same condition
NOTCH2 c.5214-10A>G Uncertain significance ★★ same condition
NOTCH2 c.874+4T>C Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/notch2-p-pro2329ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown